Ras activation is catalyzed by GEFs such as SOS that exchange bound GDP for GTP, whereas Ras inactivation is catalyzed by GAPs leading to the hydrolysis of GTP to GDP. Oncogenic mutations in KRas impair GTP hydrolysis, leading to a constitutively activated, GTP-bound mt KRas, which contributes significantly to human cancer pathogenesis and patient tumor resistance. The purpose of this research program is to identify small molecules that bind mt KRas directly and shift its state from GTP to GDP, inhibiting its ability to bind its effectors. Although the picomolar affinity for GTP and the difficulty in identifying allosteric sites have made it hard to target directly Ras, evidence for the feasibility of targeting Ras has been reported. Recently, one report provided compelling evidence of small molecules that can bind covalently to Cys, occupy a pocket composed largely of the switch II region of G12C mt KRas, and inhibit the interaction of Ras-GTP with its effectors. Other recent reports identified small molecules that inhibited SOS-mediated nucleotide exchange by binding to a pocket adjacent to the switch I/II regions of KRas. Although compounds that exclusively inhibit GDP exchange for GTP may be effective in tumors that depend on wt Ras for their malignancy, they are less likely to affect tumors with mt GTP-bound Ras.